This invention relates to aerosol dispersions of use for the administration of medicaments from an aerosol.
Medicaments have been delivered from propellant-basedaerosols in a variety of forms, for example, metered dose inhalers (MDI), topical sprays and whips, with the MDI being the most common. Since the introduction of the MDI in the mid 1950s, inhalation has become the most widely used route of administration of bronchodilators and steroids locally to the airways of asthmatic patients. Compared with oral administration of bronchodilators, inhalation via an MDI offers a rapid onset of action and a low incidence of systemic side effects.
The medicinal aerosol is dependent on the propulsive force of the propellant system used in its manufacture. Traditionally, the propellant system has consisted of perfluorinated compounds, hydrofluoroalkanes (HFAs), or a mixture of chlorofluorocarbons (CFCs) which are selected to provide the desired vapor pressure and suspension stability. While such systems may be used to deliver solubilized drug, the selected bioactive agent is typically incorporated in the form of a fine particulate to provide a dispersion in the liquefied propellant. To minimize or prevent the problem of aggregation in such systems, surfactants are often used to coat the surfaces of the bioactive agent and assist in wetting the particles with the aerosol propellant. The use of surfactants in this way to maintain substantially uniform dispersions is said to “stabilize” the suspensions. In some dispersions, the use of surfactants may not be desirable. The consistent and effective delivery of a therapeutically active compound (that is, a medicament) to a living organism is generally affected by a number of parameters beyond the actual chemical identity and pharmacological activity of the medicament.
Medicinal aerosols can be an effective way to introduce a medicament into the pulmonary system via oral or nasal inhalation, but there are a number of parameters governing medicinal aerosol compositions that affect their performance. The relative importance of these parameters can vary depending on the type of dosage form used (e.g., metered dose inhaler or MDI, dry powder inhaler, nebulizer) and the type of medicament being delivered, but will usually include such things as the concentration of medicament in the dosage form, the particle size of the aerosol that is delivered to an organism, the physicochemical stability of the composition, and the ability of particles delivered to the pulmonary system to be absorbed by the body.
In order to achieve certain desirable properties or an acceptable balance of properties, it is sometimes desirable to incorporate various excipients into a medicinal aerosol composition. Many different excipients have been suggested for use in medicinal aerosols, for such things as solubilizing medicament, improving the suspension quality of medicament, increasing the emitted particle size, etc. But many proposed excipients, while providing one or more benefits, suffer from drawbacks that make them otherwise undesirable for use, such as toxicological problems, limited propellant solubility, detrimental interactions with other product components, or limited ability to be broadly utilized.
More particularly, most medicament suspensions in any of the known propellants tend to aggregate rapidly. If the particle size of the suspended material cannot be regulated and aggregation takes place, the valve orifice of the aerosol container may clog, rendering the dispensing device inoperative or, if a metering valve is employed, it may be rendered inaccurate. This unwanted aggregation or flocculation may lead to improper dosages which can lead to undesirable results, particularly in the case of highly potent, low dose medicaments. Moreover, such rapid particle aggregation also leads to fast creaming or sedimentation of the suspension. The resulting phase separation is generally addressed by vigorously shaking the MDI device immediately before use. However, patient compliance is difficult to control and many commercially available suspensions are so unstable that even slight delays between shaking and use can affect dosage uniformity.
Hence, there is an ongoing need for new and effective excipients that are useful in medicinal aerosols, particularly pressurized medicinal aerosols using hydrofluorocarbon propellants, such as HFC-134a and HFC-227. Although research investment has been made over the last decade, formulating CFC-free pressurized metered dose inhalers that are suitable in terms of the stringent functional and therapeutic requirements today continues to be of major importance.